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In the pre-rituximab era, most (but not all) researchers reported that bulky disease had
an influence on the outcome in patients with aggressive lymphoma and diffuse large
B-cell lymphoma (DLBCL) [1–7]. Divergent results were obtained because of differences
in the patient populations studied. After R-CHOP (rituximab, cyclophosphamide,
doxorubicin, vincristine, and prednisolone) became the standard treatment, the
prognosis of DLBCL with a bulky mass was re-examined. The US Intergroup trial did not
demonstrate that tumor size was an important indicator in DLBCL patients receiving
R-CHOP therapy , and bulky disease (a mass ³10 cm in diameter) was not identified
as a prognostic factor in the Groupe d’Etude des Lymphomes de l’Adulte (GELA) Study
. However, a recent extrapolative analysis of the MabThera International Trial Group
(MInT) study found a stronger influence of the maximum size of bulky masses on the
outcome of patients in the rituximab era . Thus, the influence of a bulky mass on the
In patients with a bulky mass, residual tumor is often detected by CT at the end
of treatment, and it is sometimes difficult to determine whether additional treatment
such as radiotherapy should be performed or not. According to the NCCN guidelines
(2013 ver.1), if PET-CT is positive at the end of treatment for limited DLBCL with a
bulky mass (>10 cm), radiotherapy should be considered (Category 1). In patients with
advanced DLBCL and a bulky mass, however whether radiotherapy is required should be
determined on a case-by-case basis (Category 2B).
In the present study, we retrospectively investigated the outcome of DLBCL
patients with a bulky mass and also assessed the accuracy of predicting the prognosis
based on the post-treatment PET-CT findings.
MATERIALS AND METHODS
Bulky disease was defined as a measurable mass ³10 cm diameter or a mediastinal mass
>1/3 of the chest diameter . If a bulky mediastinal mass showed invasion of the
surrounding structures and was pathologically diagnosed as DLBCL, the patient was
considered to have primary mediastinal large B-cell lymphoma and was excluded from this
study. From February 2004 to July 2011, 201 consecutive patients who had untreated
DLBCL received R-CHOP therapy (cyclophosphamide 750 mg/m2on Day 1; doxorubicin
50 mg/m2 on Day 1; vincristine 1.4 mg/m2 on Day 1 (max 2 mg); prednisolone 60 mg/m2
patients, 29 had a bulky mass. We compared treatment outcomes between the bulky mass
group (n = 29) and the non-bulky mass group (n = 172). We also studied prognostic factors
and the accuracy of predicting the outcome based on detection of residual disease at the end
of R-CHOP therapy in the bulky mass group. The criteria of Cheson et al. were used to
assess the effectiveness of treatment  Positron emission tomography-computed
tomography (PET-CT) with 18-F-fluorodeoxyglucose was performed at 6 to 8 weeks after
abnormal uptake or minimal residual uptake. Mediastinal blood pool activity was used
as the reference to define PET positivity. If a residual mass ³2.0 cm in greatest
transverse diameter (or a smaller residual mass or normal-sized lymph node) showed
PET-CT scans were reviewed by a single nuclear medicine physician.
Overall survival (OS) was defined as the interval from diagnosis until death from any
cause or the final date of observation. Progression-free survival (PFS) was defined as the
interval from diagnosis until relapse or progression of lymphoma, death from any cause,
or the final date of observation (if progression or death did not occur). Survival was
calculated by the Kaplan-Meier method, and differences in survival were assessed by the
log-rank test. The relative risk and its 95% confidence interval (CI) were determined, as
well as P values. All P values were two-sided, with significance being accepted at P0.05.
Statistical analyses were performed with R2.10.1 software (R Foundation for Statistical
of Kanagawa Cancer Center.
The median age of the patients with a bulky mass was 65 years (range: 20–78 years). The
most frequent site of a bulky mass at presentation was the mesenteric lymph nodes
(55%) and the maximum tumor diameter was 11.5 cm (10.0–17.0 cm). The characteristics
of the 29 patients are presented in Table I. The number of patients in stages I, II, III, and
distribution between the two groups (P=0.625). The International prognostic index (IPI)
the patients, respectively. Patients with a bulky were more likely to be in poor risk
categories, though this was not statistically significant (P=0.069). Patients with a bulky
mass were significantly more likely to have a performance status (PS) ³2 (45% vs. 19%,
P=0.005), elevation of serum lactate dehydrogenase (LDH) (86% vs. 61%, P=0.007), and B
symptoms (38% vs. 17%, P=0.017).
Outcome of patients with and without a bulky mass
The median follow-up time for surviving patients was 3.2 years (range: 0.7–8.0 years).
Figure 1 shows the 3-year OS and PFS of patients who had limited disease with or
(90% [95% CI: 84–98] vs. 69% [95% CI: 45–100] [P=0.105] and 83% [95% CI: 75–92] vs.
patients who had advanced disease with or without a bulky mass. Again, there were no
significant differences between the two groups (76% [95% CI: 67–87] vs. 66% [95% CI:
43–100] [P=0.279] and 72% [95% CI: 63–83] vs. 28% [95% CI: 65–100] [P=0.096],
Prognosis of patients with a bulky mass
When prognostic factors for OS and PFS were assessed by univariate analysis, the
findings on post-treatment PET-CT were statistically associated with OS (34% [95% CI:
12–94] for PET-positive patients vs. 75% [95% CI: 43–100] for PET-negative patients
[P=0.014]) and with PFS (36% [95% CI: 18–72] vs. 83% [95% CI: 58–100], respectively
[P<0.001]) (Figure 3 and Table II). In contrast, the age, PS, LDH, stage, and extranodal
disease were not significantly associated with either OS or PFS.
PET-CT was performed before treatment in 27 patients, but not in 2 patients
with rapid disease progression. At the end of treatment, 28 patients underwent PET-CT,
excluding 1 patient with disease progression, and 14 patients had no abnormal uptake of
FDG. Although 5 (2 with limited disease and 3 with advanced disease) of the 14 patients
still had residual tumors on CT, none of them received additional treatment (including
radiation therapy) and all of them remained in remission at the end of the observation
period. The other 14 patients had abnormal FDG uptake at the completion of R-CHOP
therapy. Nine of these patients (3 with limited disease and 6 with advanced disease) still
had a bulky mass on CT, and 5 of them developed recurrence after receiving
The presence or absence of a bulky mass is not included in the IPI, which is widely used
for predicting the prognosis of DLBCL. However, a poor prognosis has been reported for
DLBCL patients with large extranodal lesions or those with tumors more than 5.0 to 10.0
cm in diameter [10,13,14]. One problem is the lack of a generally accepted definition of a
bulky mass. In the present study, we defined a bulky mass as a tumor ³10 cm diameter or
a mediastinal mass >1/3 of the chest diameter, according to the Cotswolds classification,
which is widely used for clinical staging of malignant lymphoma. As a result, we found
that DLBCL patients with a bulky mass tended to have features that were suggestive of
progressive disease, including a worse PS, B symptoms, a higher serum LDH level, and a
higher IPI risk than in the patients without a bulky mass. However, the presence of a
bulky mass was not correlated with a poor prognosis among patients with either limited
disease or advanced disease.
Among DLBCL patients with a bulky mass before treatment, regardless of
whether or not a residual mass was detected by CT after R-CHOP therapy, those who
were negative for abnormal uptake on PET-CT had a good prognosis without additional
treatment, whereas those with abnormal uptake had a poor prognosis. According to
Juweid et al., about half of the patients with DLBCL achieving PR on post-treatment CT
showed no uptake of FDG, and their progression-free survival was almost equivalent to
that of CR patients without additional treatment and was better than that of patients
with FDG uptake. There have been few reports about the outcome of DLBCL with a
bulky mass based on post-treatment PET-CT findings. Our results suggested that
performing PET-CT at the end of R-CHOP therapy may be useful for predicting the
prognosis, similar to the case for DLBCL without a bulky mass.
However, the positive predictive value of PET-CT is not so high, since judgment
of positive uptake is difficult and poor reproducibility of assessment between interpreters
has been pointed out. Although we used the efficacy criteria proposed by Cheson et al., a
five-point scale has recently been employed in clinical trials with interim PET and the
usefulness of this scale has been reported . Therefore, the criteria for assessing
efficacy should be studied further and standardization of the criteria for PET-CT
positivity should be a target for the future.
Radiotherapy for residual lesions did not seem to be important in our patients
who showed no uptake on post-treatment PET-CT at the end of R-CHOP therapy.
However, the present study was not designed to assess the usefulness of radiotherapy,
emphasizing the need for additional clinical studies.
In conclusion, the present study demonstrated that a bulky mass was not a poor
prognostic indicator for patients with DLBCL. Instead, the results of PET-CT at the end
of treatment may be useful for predicting the prognosis. Although our study had the
limitations of a retrospective design and a small number of subjects, the results
suggested that radiotherapy may not be required for a residual bulky mass if there is no
abnormal FDG uptake on PET-CT at the end of R-CHOP therapy. However, confirmation
by a prospective study is needed.
There was no funding for this study.
Potential conflict of interest
The authors have no conflict of interest to declare.
1. Shipp MA, Harrington DP, Klatt MM, Jochelson MS, Pinkus GS, Marshall JL,
Rosenthal DS, Skarin AT, Canellos GP. Identification of major prognostic subgroups
of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann
Intern Med 1986; 104: 757–765.
2. Hurvich CM, Simonoff JS, Tsai C-L. Smoothing parameter selection in
nonparametric regression using an improved Akaike information criterion. J R Stat
Soc 1998; 60: 271–293.
3. Fisher RI, DeVita VT Jr, Johnson BL, Simon R, Young RC. Prognostic factors for
advanced diff use histiocytic lymphoma following treatment with combination
chemotherapy. Am J Med 1977; 63: 177–182.
4. Danieu L, Wong G, Koziner B, Clarkson B. Predictive model for prognosis in
advanced diffuse histiocytic lymphoma. Cancer Res 1986; 46: 5372–5379.
5. Hoskins PJ, Ng V, Spinelli JJ, Klimo P, Connors JM. Prognostic variables in patients
with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 1991; 9:
6. Savage KJ, Al Rajhi N, Voss N, Paltiel C, Klasa R, Gascoyne RD, Connors JM.
Favorable outcome of primary mediastinal large B-cell lymphoma in a single
institution: the British Columbia experience. Ann Oncol 2006; 17: 123–130.
7. Tomita N, Kodama F, Motomura S, Itoh S, Ohshima R, Hyo R, Kawano T,
Hashimoto C, Takemura S, Yamazaki E, Fujita H, Fujisawa S, Ogawa K, Kanamori
H, Ishigatsubo Y. Adjuvant radiotherapy to an initial bulky mass in diffuse large
B-cell lymphoma: lack of survival benefit. Int J Lab Hematol 2008; 30: 53-57.
8. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB,
10 Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ. Rituximab-CHOP versus
CHOP alone or with maintenance rituximab in older patients with diffuse large
B-cell lymphoma. J Clin Oncol 2006; 24: 3121–3127.
9. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van
Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP
chemotherapy plus rituximab compared with CHOP alone in elderly patients with
diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242.
10. Pfreundschuh M, Ho AD, Cavallin-Stahl E, Wolf M, Pettengell R, Vasova I, Belch A,
Walewski J, Zinzani PL, Mingrone W, Kvaloy S, Shpilberg O, Jaeger U, Hansen M,
Corrado C, Scheliga A, Loeffler M, Kuhnt E; MabThera International Trial (MInT)
Group. Prognostic significance of maximum tumour (bulk) diameter in young
patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like
chemotherapy with or without rituximab: an exploratory analysis of the MabThera
International Trial Group (MInT) study. Lancet Oncol 2008; 9: 435–444.
11. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg
SA, Coltman CA, Tubiana M. Report of a committee convened to discuss the
evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin
Oncol 1989; 7: 1630–1636.
12. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B,
Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT,
Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International
Harmonization Project on Lymphoma. Revised response criteria for malignant
lymphoma. J Clin Oncol 2007; 25: 579–586.
13. Song MK, Chung JS, Sung-Yong O, Lee GW, Kim SG, Seol YM, Shin HJ, Choi YJ,
11 Cho GJ, Shin DH, Yun EY. Clinical impact of bulky mass in the patient with primary
extranodal diffuse large B cell lymphoma treated with R-CHOP therapy. Ann
Hematol 2010; 10: 985–991.
14. Fukuhara S, Watanabe T, Munakata W, Mori M, Maruyama D, Kim SW, Kobayashi
Y, Taniguchi H, Maeshima AM, Tanosaki R, Matsuno Y, Tobinai K. Bulky disease
has an impact on outcomes in primary diffuse large B-cell lymphoma of the breast: a
retrospective analysis at a single institution. Eur J Hematol 2011; 5: 434–440.
15. Juweid ME, Wiseman GA, Vose JM, Ritchie JM, Menda Y, Wooldridge JE, Mottaghy
FM, Rohren EM, Blumstein NM, Stolpen A, Link BK, Reske SN, Graham MM,
Response assessment of aggressive non-Hodgkin's lymphoma by integrated
International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron
emission tomography. J Clin Oncol 2005; 23: 4652–4661.
16. Meignan M, Gallamini A, Haioun C, Gallamini A, Haioun C. Report on the First
International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma.
2009; 50: 1257–1260.
Figure 1. Overall survival of all patients. (A) Limited disease. (B) Extensive disease.
Figure 2. Progression-free survival of all patients. (A) Limited disease. (B) Extensive
Figure 3. Overall survival and progression-free survival of patients with a bulky mass
stratified by post-treatment PET-CT findings. (A) Overall survival. (B) Progression-free
[A1]The literature review is not extensive.include more recent studies.
[A2]Was any dose modification used in these patients based with poor PS.
Was any CNS prophylaxis used in the treatment protocol
[A3]What were the time points when PET-CT was done. Was the PET CTdone initially and during interim evaluation.
[A4]Was Delta SUV taken into account while defining PET positivity. What quality standards used in the study while doing the PET-CT?
[A5]Which statistical test used to analyse nivariate analysis? Was COX regression model used in the analysis
[A6]Use percentages in parenthesis also.
[A7]Use percentages in parenthesis also.
[A8]Check the order of the data. It should have been without and with bulky mass.
[A9]The survival for advanced stage DLBCL and localized DLBCL is is high ,not matching the literature review. What could be the reasons for this improved survival?
[A10]Nine patients had bulky PET positive disease at completion of therapy. Was the re biopsy done prior to giving radiotherapy? According to present guidelines these patients should have received some form of salvage therapy along with autologous transplant & radiation.